The present invention relates to a method for activation of TRPV3 (transient receptor potential vanilloid 3), more precisely a novel use of FPP (farnesyl diphosphate) accelerating TRPV3 activation.
TRPV3 (transient receptor potential vanilloid 3), was first found in 2003 owing to the studies in the fields of human physiology and pharmacology. TRPV3 was presumed to play an essential role in maintaining survival system in various tissues. In particular, TRPV3 is expressed in skin cells and peripheral sensory nerve cells which recognize foreign stimuli. TRPV3 belongs to thermoTRP family (temperature-sensitive transient receptor potential ion channels) that is the pain receptor family recognizing temperature and painful stimuli. It is expected that temperature sensing mechanism of human can be explained by disclosing the functions of TRPV3, the pain receptor, and skin disease can be reduced by the development of a TRPV3 activity regulator. To examine TRPV3 functions and develop a TRPV3 regulator, a TRPV3 specific activator that only works for TRPV3 without affecting any other TRP receptors is required.
To understand basic techniques used for the development of a TRPV3 specific inhibitor, it is important to understand the characteristics of TRPV3. TRPV3 is an ion channel and its activation makes cations migrate into sensory neurons or skin cells, stimulating intracellular signal transduction system. For skin, this calcium signal transduction system regulates cell growth and differentiation and at last determines skin cell destiny. One of the techniques to measure TRPV3 activation is patch-clamp electrophysiological technique measuring the changes of membrane currents after amplifying thereof. And another technique to measure TRPV3 activation is to measure intracellular calcium level based on the fact that TRPV3 is involved in the migration of cations such as calcium ions. The first technique is superior in sensitivity to the second one, but the second technique is superior in high speed to the first one, so that they are complementary to each other. Such techniques to measure TRPV3 activation can be executed by the support of cell line culture technique, TRPV3 DNA control and transfection techniques. Various TRPV3 specific activator candidates are administered to TRPV3 over-expressing cells and then TRPV3 activation therein is measured to select a proper TRPV3 activator and determine its capacity.
A TRPV3 specific activator is an essential element to measure TRPV3 activation for further development of a TRPV3 regulator. However, no reports have been made so far in relation to a TRPV3 specific activator. The known TRPV3 activators so far are camphor, menthol and 2-APB (2-aminoethoxydiphenyl borate). But, 2-APB is not specific to TRPV3 and in fact it can activate other TRP receptors such as TRPV1 and TRPV2, etc, or inactivate IP3 (inositol triphosphate) receptor, suggesting that it is not very useful. Camphor and menthol can activate TRPV3 at high concentration and also activate TRPV1 or TRPM8, suggesting that they are not specific to TRPV3, either.
Wound is healed by the increase of skin cell migration and growth. So, when skin cell migration and growth is inhibited, skin disease caused by over-growth of cells such as psoriasis, lichen planus, keratosis, basal cell carcinoma, hypersensitive dermatitis, atopic dermatitis, seborrheic dermatitis, and keloid can be treated [Pani B & Singh B B, Cell Mol Life Sci. 65(2):205-211, 2008 (keloid, hypersensitive dermatitis, hereditary dermatitis, etc); Hanifin J M, J Invest Dermatol. 2008 (atopy, seborrheic dermatitis); Zhao Y et al., J Invest Dermatol. 128(9):2190-2197, 2008 (atopy, psoriasis); Bovenschen H J et al., Br J Dermatol. 153(1):72-78, 2005 (atopy, lichen planus); Brennan D et al., J Cell Sci. 120 (Pt 5):758-771, 2007 (basal cell carcinoma, keratosis); Bhoumik A et al., Proc Natl Acad Sci USA. 105(5):1674-1679, 2008 (basal cell carcinoma); Teh M T et al., J Cell Sci. 120 (Pt 2):330-339, 2007 (basal cell carcinoma); Birnbaum R Y et al., Nat Genet. 38(7):749-751, 2006 (keratosis, lichen planus); Lim C P et al., Oncogene. 25(39):5416-5425, 2006 (keloid); Lim C P et al., J Invest Dermatol. 2008 (keloid); Korean Patent No 10-0771523 (psoriasis, hypersensitive dermatitis, lichen planus, basal cell carcinoma)]. For example, calcipotriol (product name: DAIVONEX) inhibits proliferation of keratinocytes, the myoblasts of HaCat skin cells, so that it is believed to have treatment effect on the propagative skin disease such as psoriasis. In fact, it has been sold as a drug for psoriasis treatment.
The present inventors constructed cell lines expressing different TRPs and investigated their responses to FPP (farnesyl diphosphate) and other chemicals known as TRP regulators. As a result, the present inventors completed this invention by confirming that FPP activated TRPV3 specifically, so that it could be effectively used for the screening of a TRPV3 activity inhibitor, and FPP also inhibited migration and proliferation of skin cells, so that it could be effectively used for treating skin disease caused by wound healing and over-proliferation of skin cells.